A MULTILEVEL ANALYSIS OF REGION- AND SEX-SPECIFIC SIGNATURES OF BRAIN AGING AND THE IMPACT OF INTRANASAL MESENCHYMAL STEM CELL-DERIVED ON FUNCTIONAL DECLINE

Aging is a multifactorial process characterized by progressive declines in brain function and plasticity. Despite extensive investigation, the bases of region- and sex-specific vulnerability remain unclear. We combined behavioral testing with histological and molecular analyses to define multilevel signatures of physiological brain aging and to explore a non-invasive rejuvenation strategy. Male and female C57BL/6 mice were studied at 4, 14, and 24 months of age. In parallel, 20-month-old mice received four months of intranasal extracellular vesicles derived from human bone marrow mesenchymal stem cells (hMSC-EVs) or vehicle. Behavioral analyses revealed that aging impaired spatial and recognition memory and reduced motor performance, with broadly similar outcomes in both sexes. These deficits were accompanied by region-specific remodeling: dendritic spine density decreased in hippocampus and prefrontal cortex in both sexes, whereas the motor cortex showed increased spine density in males, suggesting a sex-dependent compensatory response. Inhibitory circuits also changed with age, as indicated by reduced parvalbumin-positive interneurons in hippocampus and increased perineuronal net expression in motor and prefrontal cortices. Notably, preliminary data suggest that hMSC-EVs ameliorate cognitive and motor deficits in aged mice. Together, these findings reveal region- and sex-dependent trajectories of brain aging and support intranasal hMSC-EVs as promising approach to counteract age-related functional decline.
Grant Support: PRIN2022 Ministero dell’Università e della Ricerca finanziato nell’ambito del Piano Nazionale di Ripresa e Resilienza – PNRR per la Missione 4, Componente 2, investimento 1.1 - Avviso n° 104 del 02/02/2022 Finanziato dall'Unione europea - Next Generation EU PRIN 2022. Prot. 2022BS9Y5W” CUP “J53D23012680008”.